Endothelial YAP/TAZ Signaling in Angiogenesis and Tumor Vasculature

Abstract

Solid tumors are dependent on vascularization for their growth. The hypoxic, stiff, and pro-angiogenic tumor microenvironment induces angiogenesis, giving rise to an immature, proliferative, and permeable vasculature. The tumor vessels promote tumor metastasis and complicate delivery of anti-cancer therapies. In many types of tumors, YAP/TAZ activation is correlated with increased levels of angiogenesis. In addition, endothelial YAP/TAZ activation is important for the formation of new blood and lymphatic vessels during development. Oncogenic activation of YAP/TAZ in tumor cell growth and invasion has been studied in great detail, however the role of YAP/TAZ within the tumor endothelium remains insufficiently understood, which complicates therapeutic strategies aimed at targeting YAP/TAZ in cancer. Here, we overview the upstream signals from the tumor microenvironment that control endothelial YAP/TAZ activation and explore the role of their downstream targets in driving tumor angiogenesis. We further discuss the potential for anti-cancer treatments and vascular normalization strategies to improve tumor therapies.

A dual role of YAP in driving TGFβ-mediated endothelial-to-mesenchymal transition

“…Finally, YAP depletion impaired EC proliferation and migration ( ) in agreement with previous literature ( Zhang et al, 2014 ; Kim et al, 2017 ; Neto et al, 2018 ; Boopathy and Hong, 2019 ; Hooglugt et al, 2020 ). These data showed that the established immortalized in vitro system, which is a powerful tool for the setup of some experimental conditions and allows a more controlled manipulation of cellular functions and processes, retained the major characteristics of the in vivo models and can be used for research, taking into consideration eventual trade-offs ( Pan et al, 2009 ; Lorsch et al, 2014 ).…”

A New Player in Neuroblastoma: YAP and Its Role in the Neuroblastoma Microenvironment

“…In relation to the hypoxia-inducible factor 1 (HIF1) and its ability to drive glycolysis in the setting of hypoxia, YAP binds to HIF1 alpha, forming a complex that both sustains HIF1α stability and promotes glycolysis in hepatocellular carcinoma [ 26 , 117 ]. The hypoxic environment also leads to angiogenesis and YAP signaling is involved in tumor vasculature development [ 119 ]. Nuclear YAP/TAZ (active state) is expressed in developing endothelial cells (ECs) and the remodeling vasculature [ 120 , 121 ].…”

A New Antitumor Direction: Tumor-Specific Endothelial Cells

“…Up-regulation of the tumor suppressor gene DLC1 in ECs activated YAP signal and ECs lost the contact inhibition function,which leaded to the occurrence and proliferation of angiosarcoma (84,85). YAP also controls the activation of ECs and regulates tumorigenesis and angiogenesis (86). Thus, interference with the YAP/TAZ signaling pathway is expected to suppress tumorigenesis and tumor angiogenesis (Figure 3).…”